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Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.

ABSTRACT: A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics.

SUBMITTER: Lee IY 

PROVIDER: S-EPMC3525752 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.

Lee Ill-Young IY   Gruber Todd D TD   Samuels Amanda A   Yun Minhan M   Nam Bora B   Kang Minseo M   Crowley Kathryn K   Winterroth Benjamin B   Boshoff Helena I HI   Barry Clifton E CE  

Bioorganic & medicinal chemistry 20121115 1

A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. U  ...[more]

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